The overall objective of this proposal is to develop a new type of peptide molecular conjugates that can effectively and selectively deliver transgenes into target cells. These conjugates will be produced by a combinatorial approach through rational molecular design of independent modules, characterized systematically through modeling and experimental approaches. This proposal is based on the hypothesis that these peptide molecular conjugates will have the potential for considerable flexibility, versatility and selectivity for gene delivery. The ultimate goal of this preliminary research is to develop a peptide molecular conjugate system to selectively deliver genes into target cells in vivo. It has been widely recognized that DNA delivery is the bottleneck impeding gene therapy from reliable clinical implementation. Without an efficient and selective gene delivery technology, the promise of gene therapy can never be fully realized. This proposal aims to develop an enabling technology to systematically address this issue, combining biochemical and biomedical engineering with molecular and cell biology. Because gene therapy is a broad-based medical technology that can be applied to a variety of cell and tissue systems, different applications will require a wide range of special delivery vehicles with high efficiency and selectivity. A new type of DNA-binding self-assembling peptide system (DSAPS) as a molecular conjugate gene delivery vehicle will be developed. These molecules will have three distinctive segments: 1) a receptor recognition ligand for a specific cell surface receptor; 2) a membrane fusion segment, either from a viral fusion segment or a variety of synthetic fusion peptides; and 3) a DNA binding segment with nonspecific DNA binding motif found in histones. One of the most important features of this type of delivery vehicle is that it has no DNA packaging limit. Efforts will focus on developing some model vehicles with several independent modules to deliver genes. The combination of protein engineering and bioengineering approaches represents a new paradigm in constructing delivery vehicles.